Deficiency of the so-called pulmonary surfactant (i.e., the material that reduces intra-alveolar surface tension) causes a failure of expansion of the lungs which leads to the impairment of pulmonary ventilation essential for the maintenance of life. Disorders exhibiting such a symptom are generically named "respiratory distress syndrome (hereinafter referred to briefly as RDS)". It is known that this disease frequently occurs not only in premature infants but also in adult patients with bacterial infection, gas intoxication or traumata.
In recent years, great importance has been attached to the use of a substitute for the deficient pulmonary surfactant in the treatment of RDS. A large number of previous studies on the pulmonary surfactant have established certain physicochemical criteria for such a substitute. In a brief summary, the main criteria are as follows: (1) the substitute must be capable of reducing the surface tension of physiological saline to 10 dynes/cm or less (the most important criterion); (2) the substitute must be able to become adsorbed to and spread over a gas-liquid interface rapidly; and (3) the substitute must give a good surface tension-surface area hysteresis curve (hereinafter referred to briefly as a hysteresis curve) [American Journal of Physiology, 223(3), 715, 1972; Biochimica et Biophysica Acta, 344, 241, 1974; The New England Journal of Medicine, 280, 1298, 1969].
A number of well-known materials have been reported to be useable as substitutes for the pulmonary surfactant. They include, for example, mixtures of phosphatidylcholine and phosphatidylglycerol (hereinafter referred to briefly as PC-PG mixtures; Pediatric Research, 11, 573, 1979), compositions consisting essentially of dipalmitoylphosphatidylcholine and fatty alcohols (hereinafter referred to briefly as DPPC compositions; Japanese Patent Laid-Open No. 99524/1982), and a material comprising, in specific proportions, phospholipid, neutral fat, total cholesterol, carbohydrate and protein which are all obtained from the lung tissue of mammals (hereinafter referred to briefly as TA-546; Japanese Patent Laid-Open No. 160721/'80). However, confirmatory studies carried out by the present inventors have revealed that the PC-PG mixtures are incapable of reducing the surface tension of physiological saline to 10 dynes/cm or less and that the DPPC compositions are slow in becoming adsorbed to and spreading over a gas-liquid interface and do not give a good hysteresis curve. Thus, these materials have chemical compositions consisting essentially of or containing the main components of the pulmonary surfactant but, nevertheless, do not fulfill the above-described criteria. On the other hand, TA-546 conforms to the above-described criteria. However, since its chemical composition is complicated, it is expected that TA-546 may contain undesired components exerting an influence on its pulmonary surface activity.
Specifically, per Table 1 of Tetsuro et al, U.S. Pat. No. 4,338,301, issued July 6, 1982, of overlapping inventorship herewith (and which corresponds to said Japanese Patent Laid-Open No. 160721/'80), it is clear that in addition to (1) 75.6 to 95.5% phospholipid, constituting its principal component (and which is itself composed of 63.0 to 85.5% phosphatidylcholine, 3.0 to 12.0% phosphatidylglycerol, 2.5 to 7.7% phosphatidylethanolamine, 5.7 to 7.0% sphingomyelin, 2.4 to 7.4% phosphatidylinositol and phosphatidylserine collectively, 0.5 to 2.1% lysophosphatidylcholine, and not greater than 1.0% others, TA-546 contains four other components: (2) 1.8 to 14.0% neutral lipid or neutral fat (whose content is calculated in glycerol trioleate equivalent and therefore is composed mostly of triglycerides, (3) 0.0 to 3.0% total cholesterol, (4) 0.1 to 1.5% carbohydrate, and (5) 0.5 to 5.0% protein, plus (6) 1.7 to 6.0% water, wherein the ratio of the (1) phospholipid content to the (5) protein content is 15.0 or greater, and the content of phosphatidylcholine having two saturated fatty acid residues based on the total phosphatidylcholine in the (1) phospholipid is 67.5 to 90.3%.
Hence, as to the (1) phospholipid fraction, TA-546 contains not only 63.0 to 85.5% phosphatidylcholine, but also many minor components including acid phospholipids such as phosphatidylglycerol, phosphatidylinositol and phosphatidylserine, and other phospholipids such as phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine, etc. Accordingly, it is reasonably to be expected that undesired components having no favorable effect or, more important, instead having adverse effects on the pulmonary surface activity of TA-546 may be present not only among the aforesaid four components (aside from water) but also among the minor components of the (1) phospholipid fraction.